Traumatic brain injury (TBI) is a global health problem that is financially crippling for many families because of both specialized care and lost financial income. TBI involves at least two separate injury cascades that lead to neuronal and cognitive dysfunction. The secondary injury cascade may be amenable to pharmacologic intervention but the mechanisms are complicated requiring a multi-faceted approach. Oxidative stress, loss of mitochondrial function, and neuroinflammation appear to play major roles. Naturally occurring flavonoids are unique in possessing not only tremendous free radical scavenging properties but also the ability to modulate cellular homeostasis leading to a reduction in inflammation and cell toxicity. The proposed studies will investigate the idea that Pycnogenol(r) (PYC), a combination of bioflavonoids, can significantly reduce the secondary injury cascade following TBI. This is an extremely novel approach to TBI therapy since it utilizes a family of very closely related biologically active polyphenols derived from tree bark. The first series of studies will explore the best possible dosing of PYC to maximally reduce oxidative stress and neuroinflammation following experimental TBI in rodents. The second set of studies will explore the protective qualities of PYC on mitochondrial bioenergetics and cell survival in the hippocampus following experimental TBI. Successful completion of the studies will pave the way for using PYC in more involved experimental TBI studies and contribute to the development of a rational therapy leading to a more favorable outcome. PUBLIC HEALTH RELEVANCE: The proposed studies investigate a specialized compound, called a bioflavonoid, to determine if it can help protect cells in the brain following injury. Using a well characterized animal model of traumatic brain injury, subjects are treated with the compound, Pycnogenol(r), and tested for a variety of outcome measures. Bioflavonoids are known to manifest multiple different helpful properties such as reducing oxidative stress. If the studies work, then more complex and longer term studies can be proposed, hopefully leading to a more rational therapy for brain injury.